The human journey: From man to men; theme and thematics in the fiction of Bernard Malamud.

Said yeats of his time: Things fall apart; the centre cannot hold…. Herbert Gold says of his time, our times: When the center does not hold, we try to make new centers

Signaling microdomains regulate inositol 1,4,5-trisphosphate-mediated intracellular calcium transients in cultured neurons

Author Posting. © Society for Neuroscience, 2005. This article is posted here by permission of Society for Neuroscience for personal use, not for redistribution. The definitive version was published in Journal of Neuroscience 25 (2005): 2853-2864, doi:10.1523/JNEUROSCI.4313-04.2005.Ca2+ signals in neurons use specific temporal and spatial patterns to encode unambiguous information about crucial cellular functions. To understand the molecular basis for initiation and propagation of inositol 1,4,5-trisphosphate (InsP3)-mediated intracellular Ca2+ signals, we correlated the subcellular distribution of components of the InsP3 pathway with measurements of agonist-induced intracellular Ca2+ transients in cultured rat hippocampal neurons and pheochromocytoma cells. We found specialized domains with high levels of phosphatidylinositol-4-phosphate kinase (PIPKIγ) and chromogranin B (CGB), proteins acting synergistically to increase InsP3 receptor (InsP3R) activity and sensitivity. In contrast, Ca2+ pumps in the plasma membrane (PMCA) and sarco-endoplasmic reticulum as well as buffers that antagonize the rise in intracellular Ca2+ were distributed uniformly. By pharmacologically blocking phosphatidylinositol-4-kinase and PIPKIγ or disrupting the CGB-InsP3R interaction by transfecting an interfering polypeptide fragment, we produced major changes in the initiation site and kinetics of the Ca2+ signal. This study shows that a limited number of proteins can reassemble to form unique, spatially restricted signaling domains to generate distinctive signals in different regions of the same neuron. The finding that the subcellular location of initiation sites and protein microdomains was cell type specific will help to establish differences in spatiotemporal Ca2+ signaling in different types of neurons.This work was supported by grants from the National Institutes of Health (GM63496, DK61747 to B.E.E., and MH67830 to M.F.Y.), Whitehall Foundation (M.F.Y.), German National Merit Foundation (S.N.J. and C.-U.C.), and Vetenskapsrådet, the Swedish Research Council (P.U.)

Biomimetic Transparent Eye Protection Inspired by the Carapace of an Ostracod (Crustacea)

In this study we mimic the unique, transparent protective carapace (shell) of myodocopid ostracods, through which their compound eyes see, to demonstrate that the carapace ultrastructure also provides functions of strength and protection for a relatively thin structure. The bulk ultrastructure of the transparent window in the carapace of the relatively large, pelagic cypridinid (Myodocopida) Macrocypridina castanea was mimicked using the thin film deposition of dielectric materials to create a transparent, 15 bi-layer material. This biomimetic material was subjected to the natural forces withstood by the ostracod carapace in situ, including scratching by captured prey and strikes by water-borne particles. The biomimetic material was then tested in terms of its extrinsic (hardness value) and intrinsic (elastic modulus) response to indentation along with its scratch resistance. The performance of the biomimetic material was compared with that of a commonly used, anti-scratch resistant lens and polycarbonate that is typically used in the field of transparent armoury. The biomimetic material showed the best scratch resistant performance, and significantly greater hardness and elastic modulus values. The ability of biomimetic material to revert back to its original form (post loading), along with its scratch resistant qualities, offers potential for biomimetic eye protection coating that could enhance material currently in use

Telemonitoring for Patients With Chronic Heart Failure: A Systematic Review

Background Telemonitoring, the use of communication technology to remotely monitor health status, is an appealing strategy for improving disease management. Methods and Results We searched Medline databases, bibliographies, and spoke with experts to review the evidence on telemonitoring in heart failure patients. Interventions included: telephone-based symptom monitoring (n = 5), automated monitoring of signs and symptoms (n = 1), and automated physiologic monitoring (n = 1). Two studies directly compared effectiveness of 2 or more forms of telemonitoring. Study quality and intervention type varied considerably. Six studies suggested reduction in all-cause and heart failure hospitalizations (14% to 55% and 29% to 43%, respectively) or mortality (40% to 56%) with telemonitoring. Of the 3 negative studies, 2 enrolled low-risk patients and patients with access to high quality care, whereas 1 enrolled a very high-risk Hispanic population. Studies comparing forms of telemonitoring demonstrated similar effectiveness. However, intervention costs were higher with more complex programs ($8383 per patient per year) versus less complex programs ($1695 per patient per year). Conclusion The evidence base for telemonitoring in heart failure is currently quite limited. Based on the available data, telemonitoring may be an effective strategy for disease management in high-risk heart failure patients

Observations of gas flows inside a protoplanetary gap

Gaseous giant planet formation is thought to occur in the first few million years following stellar birth. Models predict that giant planet formation carves a deep gap in the dust component (shallower in the gas). Infrared observations of the disk around the young star HD142527, at ~140pc, found an inner disk ~10AU in radius, surrounded by a particularly large gap, with a disrupted outer disk beyond 140AU, indicative of a perturbing planetary-mass body at ~90 AU. From radio observations, the bulk mass is molecular and lies in the outer disk, whose continuum emission has a horseshoe morphology. The vigorous stellar accretion rate would deplete the inner disk in less than a year, so in order to sustain the observed accretion, matter must flow from the outer-disk into the cavity and cross the gap. In dynamical models, the putative protoplanets channel outer-disk material into gap-crossing bridges that feed stellar accretion through the inner disk. Here we report observations with the Atacama Large Millimetre Array (ALMA) that reveal diffuse CO gas inside the gap, with denser HCO+ gas along gap-crossing filaments, and that confirm the horseshoe morphology of the outer disk. The estimated flow rate of the gas is in the range 7E-9 to 2E-7 Msun/yr, which is sufficient to maintain accretion onto the star at the present rate

Human subjects protection issues in QUERI implementation research: QUERI Series

<p>Abstract</p> <p>Background</p> <p>Human Subjects protections approaches, specifically those relating to research review board oversight, vary throughout the world. While all are designed to protect participants involved in research, the structure and specifics of these institutional review boards (IRBs) can and do differ. This variation affects all types of research, particularly implementation research.</p> <p>Methods</p> <p>In 2001, we began a series of inter-related studies on implementing evidence-based collaborative care for depression in Veterans Health Administration primary care. We have submitted more than 100 IRB applications, amendments, and renewals, and in doing so, we have interacted with 13 VA and University IRBs across the United States (U.S.). We present four overarching IRB-related themes encountered throughout the implementation of our projects, and within each theme, identify key challenges and suggest approaches that have proved useful. Where applicable, we showcase process aids developed to assist in resolving a particular IRB challenge.</p> <p>Results</p> <p>There are issues unique to implementation research, as this type of research may not fit within the traditional Human Subjects paradigm used to assess clinical trials. Risks in implementation research are generally related to breaches of confidentiality, rather than health risks associated with traditional clinical trials. The implementation-specific challenges discussed are: external validity considerations, Plan-Do-Study-Act cycles, risk-benefit issues, the multiple roles of researchers and subjects, and system-level unit of analysis.</p> <p>Discussion</p> <p>Specific aspects of implementation research interact with variations in knowledge, procedures, and regulatory interpretations across IRBs to affect the implementation and study of best methods to increase evidence-based practice. Through lack of unambiguous guidelines and local liability concerns, IRBs are often at risk of applying both variable and inappropriate or unnecessary standards to implementation research that are not consistent with the spirit of the Belmont Report (a summary of basic ethical principles identified by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research), and which impede the conduct of evidence-based quality improvement research. While there are promising developments in the IRB community, it is incumbent upon implementation researchers to interact with IRBs in a manner that assists appropriate risk-benefit determinations and helps prevent the process from having a negative impact on efforts to reduce the lag in implementing best practices.</p

Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy

Background: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. Methods: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. Results: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 ± 4%, 31 ± 5%, and 32 ± 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 ± 4%) compared to NB90 MT (34 ± 5%, p = 0.026) and to no consolidation (35 ± 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. Conclusions: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective

Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence

Ancient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations

Hubble Space Telescope NICMOS Polarization Observations of Three Edge-on Massive YSOs

Massive young stellar objects (YSOs), like low-mass YSOs, appear to be surrounded by optically thick envelopes and/or disks and have regions, often bipolar, that are seen in polarized scattered light at near-infrared wavelengths. We are using the 0.2'' spatial resolution of NICMOS on Hubble Space Telescope to examine the structure of the disks and outflow regions of massive YSOs in star-forming regions within a few kpc of the Sun. Here we report on 2 micron polarimetry of NGC 6334 V and S255 IRS1. NGC 6334 V consists of a double-lobed bright reflection nebula seen against a dark region, probably an optically thick molecular cloud. Our polarization measurements show that the illuminating star lies ~ 2'' south of the line connecting the two lobes; we do not detect this star at 2 micron, but there are a small radio source and a mid-infrared source at this location. S255 IRS1 consists of two YSOs (NIRS1 and NIRS3) with overlapping scattered light lobes and luminosities corresponding to early B stars. Included in IRS1 is a cluster of stars from whose polarization we determine the local magnetic field direction. Neither YSO has its scattered light lobes aligned with this magnetic field. The line connecting the scattered light lobes of NIRS1 is twisted symmetrically around the star; the best explanation is that the star is part of a close binary and the outflow axis of NIRS1 is precessing as a result of non-coplanar disk and orbit. The star NIRS3 is also offset from the line connecting its two scattered light lobes. We suggest that all three YSOs show evidence of episodic ejection of material as they accrete from dense, optically thick envelopes.Comment: 39 pages, 7 figures, 4 tables To be published in The Astrophysical Journa

Adrenocortical tumors and pheochromocytoma/paraganglioma initially mistaken as neuroblastoma — experiences from the GPOH-MET registry

In children and adolescents, neuroblastoma (NBL), pheochromocytoma (PCC), and adrenocortical tumors (ACT) can arise from the adrenal gland. It may be difficult to distinguish between these three entities including associated extra-adrenal tumors (paraganglioma, PGL). Precise discrimination, however, is of crucial importance for management. Biopsy in ACT or PCC is potentially harmful and should be avoided whenever possible. We herein report data on 10 children and adolescents with ACT and five with PCC/PGL, previously mistaken as NBL. Two patients with adrenocortical carcinoma died due to disease progression. Two (2/9, missing data in one patient) patients with a final diagnosis of ACT clearly presented with obvious clinical signs and symptoms of steroid hormone excess, while seven patients did not. Blood analyses indicated increased levels of steroid hormones in one additional patient; however, urinary steroid metabolome analysis was not performed in any patient. Two (2/10) patients underwent tumor biopsy, and in two others tumor rupture occurred intraoperatively. In 6/10 patients, ACT diagnosis was only established by a reference pediatric pathology laboratory. Four (4/5) patients with a final diagnosis of PCC/PGL presented with clinical signs and symptoms of catecholamine excess. Urine tests indicated possible catecholamine excess in two patients, while no testing was carried out in three patients. Measurements of plasma metanephrines were not performed in any patient. None of the five patients with PCC/PGL received adrenergic blockers before surgery. In four patients, PCC/PGL diagnosis was established by a local pathologist, and in one patient diagnosis was revised to PGL by a pediatric reference pathologist. Genetic testing, performed in three out of five patients with PCC/PGL, indicated pathogenic variants of PCC/PGL susceptibility genes. The differential diagnosis of adrenal neoplasias and associated extra-adrenal tumors in children and adolescents may be challenging, necessitating interdisciplinary and multidisciplinary efforts. In ambiguous and/or hormonally inactive cases through comprehensive biochemical testing, microscopical complete tumor resection by an experienced surgeon is vital to preventing poor outcome in children and adolescents with ACT and/or PCC/PGL. Finally, specimens need to be assessed by an experienced pediatric pathologist to establish diagnosis